tbuckley/cabot-search huggingface dataset:
Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections
Authors: Jelmer H van Puffelen, Boris Novakovic, Liesbeth van Emst, Denise Kooper, Tahlita C M Zuiverloon, Ursula T H Oldenhof, J Alfred Witjes, Tessel E Galesloot, Alina Vrieling, Katja K H Aben, Lambertus A L M Kiemeney, Egbert Oosterwijk, Mihai G Netea, Joost L Boormans, Antoine G van der Heijden, Leo A B Joosten, Sita H Vermeulen
Journal: Journal for ImmunoTherapy of Cancer (2023)

BCG is recommended as intravesical immunotherapy to reduce the risk of tumor recurrence in patients with non-muscle invasive bladder cancer (NMIBC). Currently, it is unknown whether intravesical BCG application induces trained immunity.The aim of this research was to determine whether BCG immunotherapy induces trained immunity in NMIBC patients. We conducted a prospective observational cohort study in 17 NMIBC patients scheduled for BCG therapy and measured trained immunity parameters at 9 time points before and during a 1-year BCG maintenance regimen. Ex vivo cytokine production by peripheral blood mononuclear cells, epigenetic modifications, and changes in the monocyte transcriptome were measured. The frequency of respiratory infections was investigated in two larger cohorts of BCG-treated and non-BCG treated NMIBC patients as a surrogate measurement of trained immunity. Gene-based association analysis of genetic variants in candidate trained immunity genes and their association with recurrence-free survival and progression-free survival after BCG therapy was performed to investigate the hypothesized link between trained immunity and clinical response.We found that intravesical BCG does induce trained immunity based on an increased production of TNF and IL-1β after heterologous ex vivo stimulation of circulating monocytes 6-12 weeks after intravesical BCG treatment; and a 37% decreased risk (OR 0.63 (95% CI 0.40 to 1.01)) for respiratory infections in BCG-treated versus non-BCG-treated NMIBC patients. An epigenomics approach combining chromatin immuno precipitation-sequencing and RNA-sequencing with in vitro trained immunity experiments identified enhanced inflammasome activity in BCG-treated individuals. Finally, germline variation in genes that affect trained immunity was associated with recurrence and progression after BCG therapy in NMIBC.We conclude that BCG immunotherapy induces trained immunity in NMIBC patients and this may account for the protective effects against respiratory infections. The data of our gene-based association analysis suggest that a link between trained immunity and oncological outcome may exist. Future studies should further investigate how trained immunity affects the antitumor immune responses in BCG-treated NMIBC patients.
The effect of immunomodulators on seroconversion after BNT162b2 and AZD1222 vaccines in patients with immune-mediated inflammatory diseases: a prospective cohort study
Authors: Ali Al-Janabi, Amelle Ra, Zoe Littlewood, Amy C Foulkes, Hamish J A Hunter, Hector Chinoy, Christopher A Moriarty, Kimme L Hyrich, Jimmy K Limdi, Zenas Z N Yiu, Christopher E M Griffiths, Richard B Warren
Journal: British Journal of Dermatology (2022)

Biologic and nonbiologic immunomodulators, used to treat immune-mediated inflammatory diseases (IMIDs), could impair the immune response to COVID-19 vaccines and thus vaccine effectiveness.Our objective was to investigate the association between biologic and nonbiologic immunomodulators and seroconversion following the first and second dose of COVID-19 vaccines in patients with IMIDs.Serum samples were collected following the first or second dose of the BNT162b2 or AZD1222 vaccines from patients receiving biologic and/or nonbiologic immunomodulators for one or more of psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease or systemic lupus erythematosus. Seroconversion was defined as a positive Roche Elecsys® Anti-SARS-CoV-2 S (spike protein subunit S1/receptor binding domain) immunoassay (≥ 0.8 U mL-1). Association between immunomodulator exposure and seroconversion was assessed using logistic regression, adjusting for age and sex.After excluding those with prior COVID-19, post-first vaccine dose samples from 193 participants and post-second dose samples from 312 participants were included in the analysis. Following the first vaccine dose, 17.6% (n = 34) of participants did not seroconvert. Seroconversion was reduced for those on nonbiologic [adjusted odds ratio (OR) 0.29, 95% confidence interval (CI) 0.12-0.69] or combined nonbiologic and biologic treatment (adjusted OR 0.14, 95% CI 0.045-0.45) compared with those on biologic monotherapy. Subgroup analysis demonstrated reduced odds of seroconversion in those on methotrexate (adjusted OR 0.097, 95% CI 0.19-0.49) or prednisolone treatment (adjusted OR 0.044, 95% CI 0.002-1.00) relative to tumour necrosis factor-α inhibitor monotherapy. No participants receiving rituximab (n < 5) seroconverted after the first vaccine dose. Following the second vaccine dose, 1.6% of all participants did not seroconvert. Non-seroconversion was associated with receiving rituximab (n = 3 of 4) compared with those receiving other therapies (n = 2 of 308, P < 0.001). Post hoc analyses demonstrated that non-seroconversion was associated with age [adjusted OR 0.18, 95% CI 0.037-0.93 for those aged 60 years and over (reference category age 18-39 years)], but not sex, ethnicity or vaccine type.Treatment with nonbiologics, particularly methotrexate, is associated with impaired seroconversion following two BNT162b2 or AZD1222 vaccine doses, in patients with IMIDs. These findings are consistent with those of other published studies. While this could indicate reduced protection against COVID-19, the immunological parameters that correlate most closely with vaccine effectiveness need to be defined to reach this conclusion.
Trojan-horse silk fibroin nanocarriers loaded with a re-call antigen to redirect immunity against cancer
Authors: Elia Bari, Francesca Ferrera, Tiziana Altosole, Sara Perteghella, Pierluigi Mauri, Rossana Rossi, Giulia Passignani, Luca Mastracci, Martina Galati, Giuseppina Iliana Astone, Maddalena Mastrogiacomo, Patrizio Castagnola, Daniela Fenoglio, Dario Di Silvestre, Maria Luisa Torre, Gilberto Filaci
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background The current challenge for immunotherapies is to generate effective antitumor immunity. Since tumor immune escape mechanisms do not impact pre-existing and consolidated immune responses, we tested the hypothesis of redirecting a pregenerated immunity to cancer: to recall a non-tumor antigen response against the tumor, silk fibroin nanoparticles (SFNs) have been selected as ‘Trojan-horse’ carriers, promoting the antigen uptake by the tumor cells. Methods SFNs have been loaded with either ovalbumin (OVA) or CpG oligonucleotide (CpG) as antigen or adjuvant, respectively. In vitro uptake of SFNs by tumor (B16/F10 melanoma and MB49 bladder cancer) or dendritic cells, as well as the presence of OVA-specific T cells in splenic and tumor-infiltrating lymphocytes, were assessed by cytometric analyses. Proof-of-concept of in vivo efficacy was achieved in an OVA-hyperimmune B16/F10 murine melanoma model: SFNs-OVA or SFNs-CpG were injected, separately or in association, into the subcutaneous peritumoral area. Cancer dimensions/survival time were monitored, while, at the molecular level, system biology approaches based on graph theory and experimental proteomic data were performed. Results SFNs were efficiently in vitro uptaken by cancer and dendritic cells. In vivo peritumor administration of SFNs-OVA redirected OVA-specific cytotoxic T cells intratumorally. Proteomics and systems biology showed that peritumoral treatment with either SFNs-OVA or SFNs-CpG dramatically modified tumor microenvironment with respect to the control (CTR), mainly involving functional modules and hubs related to angiogenesis, inflammatory mediators, immune function, T complex and serpins expression, redox homeostasis, and energetic metabolism. Both SFNs-OVA and SFNs-CpG significantly delayed melanoma growth/survival time, and their effect was additive. Conclusions Both SFNs-OVA and SFNs-CpG induce effective anticancer response through complementary mechanisms and show the efficacy of an innovative active immunotherapy approach based on the redirection of pre-existing immunity against cancer cells. This approach could be universally applied for solid cancer treatments if translated into the clinic using re-call antigens of childhood vaccination.
Association between healthy lifestyle and memory decline in older adults: 10 year, population based, prospective cohort study
Authors: Jianping Jia, Tan Zhao, Zhaojun Liu, Yumei Liang, Fangyu Li, Yan Li, Wenying Liu, Fang Li, Shengliang Shi, Chunkui Zhou, Heyun Yang, Zhengluan Liao, Yang Li, Huiying Zhao, Jintao Zhang, Kunnan Zhang, Minchen Kan, Shanshan Yang, Hao Li, Zhongling Liu, Rong Ma, Jihui Lv, Yue Wang, Xin Yan, Furu Liang, Xiaoling Yuan, Jinbiao Zhang, Serge Gauthier, Jeffrey Cummings
Journal: BMJ (2023)

Abstract Objective To identify an optimal lifestyle profile to protect against memory loss in older individuals. Design Population based, prospective cohort study. Setting Participants from areas representative of the north, south, and west of China. Participants Individuals aged 60 years or older who had normal cognition and underwent apolipoprotein E (APOE) genotyping at baseline in 2009. Main outcome measures Participants were followed up until death, discontinuation, or 26 December 2019. Six healthy lifestyle factors were assessed: a healthy diet (adherence to the recommended intake of at least 7 of 12 eligible food items), regular physical exercise (≥150 min of moderate intensity or ≥75 min of vigorous intensity, per week), active social contact (≥twice per week), active cognitive activity (≥twice per week), never or previously smoked, and never drinking alcohol. Participants were categorised into the favourable group if they had four to six healthy lifestyle factors, into the average group for two to three factors, and into the unfavourable group for zero to one factor. Memory function was assessed using the World Health Organization/University of California-Los Angeles Auditory Verbal Learning Test, and global cognition was assessed via the Mini-Mental State Examination. Linear mixed models were used to explore the impact of lifestyle factors on memory in the study sample. Results 29 072 participants were included (mean age of 72.23 years; 48.54% (n=14 113) were women; and 20.43% (n=5939) were APOE ε4 carriers). Over the 10 year follow-up period (2009-19), participants in the favourable group had slower memory decline than those in the unfavourable group (by 0.028 points/year, 95% confidence interval 0.023 to 0.032, P&lt;0.001). APOE ε4 carriers with favourable (0.027, 95% confidence interval 0.023 to 0.031) and average (0.014, 0.010 to 0.019) lifestyles exhibited a slower memory decline than those with unfavourable lifestyles. Among people who were not carriers of APOE ε4, similar results were observed among participants in the favourable (0.029 points/year, 95% confidence interval 0.019 to 0.039) and average (0.019, 0.011 to 0.027) groups compared with those in the unfavourable group. APOE ε4 status and lifestyle profiles did not show a significant interaction effect on memory decline (P=0.52). Conclusion A healthy lifestyle is associated with slower memory decline, even in the presence of the APOE ε4 allele. This study might offer important information to protect older adults against memory decline. Trial registration ClinicalTrials.gov NCT03653156 .
Healthy lifestyles for dementia prevention
Authors: Séverine Sabia, Archana Singh-Manoux
Journal: BMJ (2023)

Ageing is accompanied by a decline in several measures of cognitive function, such as memory, reasoning, and psychomotor speed.Differences in the rate of change in cognitive function can be substantial between individuals, 1 highlighting the importance of identifying modifiable factors that are associated with favourable cognitive ageing trajectories.An impaired cognitive status can affect the lives of individuals and their ability to live independently but this issue is also a hallmark of Alzheimer's disease and related dementias.Lifestyle factors have attracted much attention as potential targets for prevention, including in a Lancet commission for dementia prevention, 2 which lists 12 modifiable risk factors, of which three are related to lifestyle: alcohol consumption (>21 units/week), smoking, and physical inactivity.The linked study by Jia and colleagues (doi:10.1136/bmj-2022-0729691) 3 investigated the association between a healthy lifestyle and memory decline over 10 years among 29 000 participants (49% were women, mean age was 72.2 years at baseline) in the China Cognition and Ageing Study.The authors calculated a healthy lifestyle score combining six factors: healthy diet, regular physical exercise, active social contact, active cognitive activity, not smoking, and never drinking alcohol.The resulting score, ranging from zero to six healthy factors, was categorised as favourable (four to six factors), average (two to three), or unfavourable (zero to one).
Clinical utility of circulating tumor DNA sequencing with a large panel: a National Center for Precision Medicine (PRISM) study
Authors: A. Bayle, L. Belcaid, M. Aldea, D. Vasseur, F. Peyraud, C. Nicotra, A. Geraud, M. Sakkal, L. Seknazi, L. Cerbone, F. Blanc-Durand, J. Hadoux, F. Mosele, M. Tagliamento, A. Bernard-Tessier, B. Verret, C. Smolenschi, R. Clodion, N. Auger, P.M. Romano, A. Gazzah, M.N. Camus, J. Micol, O. Caron, A. Hollebecque, Y. Loriot, B. Besse, L. Lacroix, E. Rouleau, S. Ponce, J.C. Soria, F. Barlesi, F. Andre, A. Italiano
Journal: Annals of Oncology (2023)
Haemostasis in cirrhosis: Understanding destabilising factors during acute decompensation
Authors: Alberto Zanetto, Patrick Northup, Lara Roberts, Marco Senzolo
Journal: Journal of Hepatology (2023)

Hospitalised patients with decompensated cirrhosis are in a rebalanced haemostatic state due to a parallel decline in both pro- and anti-haemostatic pathways. However, this rebalanced haemostatic state is highly susceptible to perturbations and may easily tilt towards hypocoagulability and bleeding. Acute kidney injury, bacterial infections and sepsis, and progression from acute decompensation to acute-on-chronic liver failure are associated with additional alterations of specific haemostatic pathways and a higher risk of bleeding. Unfortunately, there is no single laboratory method that can accurately stratify an individual patient's bleeding risk and guide pre-procedural prophylaxis. A better understanding of haemostatic alterations during acute illness would lead to more rational and individualised management of hospitalised patients with decompensated cirrhosis. This review will outline the latest findings on haemostatic alterations driven by acute kidney injury, bacterial infections/sepsis, and acute-on-chronic liver failure in these difficult-to-treat patients and provide evidence supporting more tailored management of bleeding risk.
Case 3-2023: A 16-Year-Old Girl with Abdominal Pain and Bloody Diarrhea
Authors: Stacy A. Kahn, Maureen M. Leonard, Sjirk J. Westra, Jonathan S. Hausmann, Sarah B. Mueller
Journal: New England Journal of Medicine (2023)

A 16-year-old girl was admitted with abdominal pain and bloody diarrhea of 5 weeks' duration. Colonoscopy revealed multiple friable lesions in the sigmoid colon. A diagnostic test was performed.
Another Victory for Patients with Hemophilia
Authors: Cindy Leissinger
Journal: New England Journal of Medicine (2023)

Congenital hemophilia A is a rare bleeding disorder caused by a mutation in the gene encoding factor VIII, resulting in a deficiency of factor VIII activity. Severe hemophilia (factor VIII activity level, <1%) is characterized by repetitive bleeding into joints beginning in early childhood and poses a major risk of life-threatening hemorrhage. Moderate hemophilia (factor VIII activity level, 1 to 5%) is associated with less frequent joint and soft-tissue bleeding related to mild trauma. Replacement therapy with the use of factor VIII concentrates restores hemostasis by raising levels of factor VIII activity and is effective in the treatment of . . .
Potentiating antibody-dependent killing of cancers with CAR T cells secreting CD47-SIRPα checkpoint blocker
Authors: Megan M. Dacek, Keifer G. Kurtz, Patrick Wallisch, Stephanie A. Pierre, Shireen Khayat, Christopher M. Bourne, Thomas J. Gardner, Kristen C. Vogt, Nica Aquino, Anas Younes, David A. Scheinberg
Journal: Blood (2023)
Biomaterials-Mediated Engineering of the Immune System
Authors: Coralie Backlund, Sasan Jalili-Firoozinezhad, Byungji Kim, Darrell J. Irvine
Journal: Annual Review of Immunology (2023)

Modulation of the immune system is an important therapeutic strategy in a wide range of diseases, and is fundamental to the development of vaccines. However, optimally safe and effective immunotherapy requires precision in the delivery of stimulatory cues to the right cells at the right place and time, to avoid toxic overstimulation in healthy tissues or incorrect programming of the immune response. To this end, biomaterials are being developed to control the location, dose, and timing of vaccines and immunotherapies. Here we discuss fundamental concepts of how biomaterials are used to enhance immune modulation, and evidence from preclinical and clinical studies of how biomaterials-mediated immune engineering can impact the development of new therapeutics. We focus on immunological mechanisms of action and in vivo modulation of the immune system, and we also discuss challenges to be overcome to speed translation of these technologies to the clinic.
Delineating epileptogenic networks using brain imaging data and personalized modeling in drug-resistant epilepsy
Authors: Huifang E. Wang, Marmaduke Woodman, Paul Triebkorn, Jean-Didier Lemarechal, Jayant Jha, Borana Dollomaja, Anirudh Nihalani Vattikonda, Viktor Sip, Samuel Medina Villalon, Meysam Hashemi, Maxime Guye, Julia Makhalova, Fabrice Bartolomei, Viktor Jirsa
Journal: Science Translational Medicine (2023)

Precise estimates of epileptogenic zone networks (EZNs) are crucial for planning intervention strategies to treat drug-resistant focal epilepsy. Here, we present the virtual epileptic patient (VEP), a workflow that uses personalized brain models and machine learning methods to estimate EZNs and to aid surgical strategies. The structural scaffold of the patient-specific whole-brain network model is constructed from anatomical T1 and diffusion-weighted magnetic resonance imaging. Each network node is equipped with a mathematical dynamical model to simulate seizure activity. Bayesian inference methods sample and optimize key parameters of the personalized model using functional stereoelectroencephalography recordings of patients’ seizures. These key parameters together with their personalized model determine a given patient’s EZN. Personalized models were further used to predict the outcome of surgical intervention using virtual surgeries. We evaluated the VEP workflow retrospectively using 53 patients with drug-resistant focal epilepsy. VEPs reproduced the clinically defined EZNs with a precision of 0.6, where the physical distance between epileptogenic regions identified by VEP and the clinically defined EZNs was small. Compared with the resected brain regions of 25 patients who underwent surgery, VEP showed lower false discovery rates in seizure-free patients (mean, 0.028) than in non–seizure-free patients (mean, 0.407). VEP is now being evaluated in an ongoing clinical trial (EPINOV) with an expected 356 prospective patients with epilepsy.
Immune-Epithelial Cross Talk in Regeneration and Repair
Authors: Laure Guenin-Mace, Piotr Konieczny, Shruti Naik
Journal: Annual Review of Immunology (2023)

The epithelial tissues that line our body, such as the skin and gut, have remarkable regenerative prowess and continually renew throughout our lifetimes. Owing to their barrier function, these tissues have also evolved sophisticated repair mechanisms to swiftly heal and limit the penetration of harmful agents following injury. Researchers now appreciate that epithelial regeneration and repair are not autonomous processes but rely on a dynamic cross talk with immunity. A wealth of clinical and experimental data point to the functional coupling of reparative and inflammatory responses as two sides of the same coin. Here we bring to the fore the immunological signals that underlie homeostatic epithelial regeneration and restitution following damage. We review our current understanding of how immune cells contribute to distinct phases of repair. When unchecked, immune-mediated repair programs are co-opted to fuel epithelial pathologies such as cancer, psoriasis, and inflammatory bowel diseases. Thus, understanding the reparative functions of immunity may advance therapeutic innovation in regenerative medicine and epithelial inflammatory diseases.
353 Amlitelimab reduces serum IL-13 in a phase 2a clinical trial in atopic dermatitis without impacting T-cell expansion in a T-cell recall assay
Authors: Stephan Weidinger, Michael Cork, Adam  Reich, Thomas Bieber, Davide  Lucchesi, Natalie  Rynkiewicz, Richard C A   Sainson, Ron  Chen, Francesca Prandi, Cassandra  van Krinks, Marisa Stebegg, Ben  Porter-Brown
Journal: British Journal of Dermatology (2023)

Abstract Amlitelimab (SAR445229), a fully human non-depleting, non-cytotoxic, monoclonal antibody, binds to OX40Ligand (OX40L) on antigen-presenting cells (APC) to block OX40-OX40L interactions. In a 16-week, double-blind, Phase 2a trial (NCT03754309), amlitelimab induced clinically meaningful disease activity improvement in patients with moderate-to-severe atopic dermatitis (AD). To assess the effects of amlitelimab on interleukin (IL)-13 and T-cell recall responses. In the trial, 89 patients were randomized to amlitelimab low dose (LD; 200 mg loading/100 mg maintenance every 4 weeks [Q4W]), high dose (HD; 500 mg loading/250 mg maintenance Q4W), or placebo. Serum IL-13 levels were assessed by single molecule immunoassay (259 samples). Using human peripheral blood mononuclear cells from five healthy donors, a T-cell recall assay was performed. At baseline in the trial, IL-13 levels significantly correlated with disease severity (Eczema Area and Severity Index; r = 0.4784, P &amp;lt; 0.0001). Week 16 IL-13 levels were significantly reduced with amlitelimab vs. baseline but not placebo (median fold change [95% confidence interval, CI] from baseline to week 16 with P-values based on two-way Analysis of Variance [ANOVA] of log10-transformed fold change for patients with a complete dataset at week 16: LD 0.345 [0.23–0.44], P &amp;lt; 0.0001; HD 0.390 [0.30–0.63], P = 0.0002; placebo 0.835 [0.34–1.12], P = 0.1544). In a T-cell recall assay, amlitelimab significantly reduced IL-13 protein levels at days 3 and 6 without negatively impacting T-cell expansion, based on the percentage of proliferating CD4+ T-cells vs. isotype control. Amlitelimab decreased IL-13 levels in patients with AD and in a T-cell recall assay without negative effects on T-cell expansion, thus reducing inflammation without blocking T-cell proliferation during recall responses.